3-keto-7(alpha,beta)-loweralkyl-delta5 steroids and process for preparing same

ABSTRACT

NOVEL 7((A,B)-LOWERALKYL-3-KETO-$5-ANDROSTANES AND 7(A,B)-LOWERALKYL-3-KETO-$5-PREGNANES HAVING ANABOLIC, ANDROGENIC, CLAUDOGENIC, PROGESTATIONAL AND ANTI-PROGESTATIONAL PROPERTIES ARE PREPARED BY REACTING 3-KETO-4,6-DIENIC ANDROSTANES AND PREGNANES WITH ORGANOCOPPER REAGENTS SUCH AS DIALKYLLITHIUM CUPRATE. THE ISOMERIZATION OF THESE COMPOUNDS TO YIELD 7(A,B)-LOWERALKYL-3-KETO-$4-STEROIDS IS ALSO DESCRIBED.

United States Patent "ice 3,833,621 3-KETO-7(a, 8)-LOWERALKYL-A STEROIDS AND PROCESS FOR PREPARHNG SAME Joyce F. Grunwell, Hamilton, and Harvey D. Benson and Vladimir Petrow, Cincinnati, Ohio, assigners to Richardson-Merrell Inc., New York, N.Y. No Drawing. Filed Mar. 20, 1972, Ser. No. 236,186

Int. Cl. C07c 169/22, 169/34 US. Cl. 260397.4 11 Claims ABSTRACT OF THE DESCLOSURE DISCUSSION OF THE PRIOR ART Prior to the present invention the preparation of 3-keto- 7-alkylA -steroids has been achieved via the 1,6 addition of a suitable Grignard reagent to a 3-keto-4,6-dienic steroid substrate generally via the addition of cuprous chloride or an equivalent catalyst to promote a 1,6-addition to the steroid substrate. Thus, for example, U.S. Pat. 3,341,557 to Babcock and Campbell, teaches the preparation of 173- hydroxy 3 keto-7-methyl-A -androstanes via a 1,6 Grignard addition to the corresponding 17-hydr0Xy-3- keto-4,6-androstadienes.

The prior art also teaches the preparation of 7 (a t?)- methyl-3-keto 17,20:20,21 bis-methylenedioxy A pregnatriene via a Grignard addition reaction as described by Kerb and Wiechert, Chemische Berichte 96, 2772-3 1969). No other 7(11,3)-loweralkyl-3-keto-androstanes or corresponding pregnanes which possess unsaturation in the A position are known to applicants. The prior art also teaches the addition of organometallic reagents, in particular the addition of dimethyllithium cuprates to conjugated tetrahydronaphthalenedienones to produce 1,4 as well as 1,6 addition adducts, as reported by Marshall et. al., Tetrahedron Letters 41, 37958 (1971).

The addition of organocopper rea ents to 3-keto-4,6- dienic steroidal substrates, however, has heretofore been unknown. Surprisingly, it has now been discovered that the addition of certain organocopper reagents to 3-keto- 4,6-androstadienes and 3-keto-4,6-pregnadienes results in the selective alkylation of the 7-position, to yield 7(a,p)- lower alkyl-3-keto-A -steroids.

These novel 7( ,5)-loWeralkyl-3-keto-A -androstanes and 70x43)-loweralkyl-3-keto-A -pregnanes can be readily isomerized to the corresponding 7 (11,5)-lower-alkyl-3-keto- M-steroids, which reaction can be performed in situ if desired. Because of the convenience and high yields obtained, this process of preparing 7(ot,fl) loweralkyl-3-keto-A steroids via the corresponding A steroids represents a preferred method for their preparation.

SUMMARY OF THE INVENTION This invention relates to the synthesis of an important class of new steroid compounds. More particularly this invention relates to the class of 7(11,,8)-loweralkyl-3-keto- A -steroids belonging to the androstane and pregnane series, to a novel process for their preparation, and to a process for converting such steroids to the corresponding 7 01.5 -alkyl-3-keto-A -steroids.

The androstane series of compounds claimed to be Within the scope of the present invention includes compounds 3,833,621 Patented Sept. 3, 1974 having the androstant, 19-nor-androstan, 9 8;10a-andr'o stane and D-homo-androstane configuration and may be illustratively represented by the following general formula;

5 Rs w RE i ---R1 R 17 R2 5 16' 10 2 R1 om n Ow MR4 R: a I

wherein R represents a member of the group consisting of hydrogen and (0L,}8)-1'1'llhyl with the proviso that when R is a-methyl the 9-hydrogen is in the beta configuration and when R, is B-methyl the 9-hydrogen is in the alpha configuration;

R is individually selected from the group consistinglof hydrogen and (c m-methyl;

R is hydrogen and methyl;

R is an (a, 8)-loweralkyl group having from 1 to 3 carbon atoms;

R is hydrogen and oxo;

R is hydrogen, methyl and ethyl;

R represents a member of the group consisting of hydrogen, loweralkyl, alkenyl, alkynyl, alkadienyl, alkenylnyl and alkadiynyl having from 1 to 6 carbon atoms;

R is selected from the group consisting of hydrogen, 1- cyclopenten-l-yloxy, l-methoxycyclohexyloxy, 2-tetra- 3g hydropyranyloxy and the group -OR wherein R represents hydrogen and an acyl radical having from 1 to 12 carbon atoms, with the proviso that R, and R cannot both by hydrogen that when R; is unsaturated R cannot be O-acyl and with the further proviso that R and R when taken together are oxo or a cyclic ethylene acetal; and n is the integer 1.

The pregnane series of compounds contemplated to be within the scope of the present invention include compounds having the pregnane, 19-nor-pregnane, 9,8210apregnane and D-homo-pregnane ring systems. These compounds may be illustratively represented by the follow ing general formula:

R represents a member of the group consisting of hydrogen and (a,;3)-methyl, with the proviso thatvvheri R is a-methyl the 9-hydrogen is in the'beta configure tion, and when R is B-methyl, the 9-hydrogen is'in the alpha configuration;

R is individually selected from the group consisting of hydrogen and (c m-methyl;

R is hydrogen and methyl;

R is an (a,fl)-loweralkyl group having from 1 to 3 carbon atoms;

R is hydrogen and oxo;

R is hydrogen, methyl and ethyl;

R is hydrogen, methyl and methylene;

R is selected from the group consisting of hydrogen, methyl, ethyl, 2-tetrahydropyranyloxy and the group -OR where R represents hydrogen, a loweralkyl group having from 1 to 3 carbon atoms, and an acyl radical having from 1 to 12 carbon atoms, with the proviso that when R is methylene, R cannot be the O-acyl group, and with the further proviso that R and R when taken together represent the 160:, I'M-alkylidenedioxy group wherein A and B are loweralkyl groups having from 1 to 4 carbon atoms;

R is selected from the group consisting of hydrogen, 1- cyclopenten-l-yloxy, l-methoxycyclohexyloxy, Z-tetrahydropyranyloxy, and the group OR wherein R represents hydrogen and an acyl radical having from 1 to 12 carbon atoms, and which when taken together with R is oxo; and

R 5 is hydrogen with the proviso that R and R cannot both be hydrogen, and which when taken together with R is oxo; and

n is the integer 1.

Generally speaking the compound of this invention are crystalline solids which are insoluble in Water. They are crystallizable from many inert organic solvents such as alcohol, chloroform, acetone, toluene, benzene-ether, acetone-petroleum ether or acetone-benzene.

This invention also describes a novel process by which these compounds can be prepared. In contrast to the behavior of alkyl Grignards, it has been discovered that diloweralkyllithiumcuprates, loweralkylcoppertrialkylphosp'hite complexes or loweralkylcoppertrialkylphosphine complexes, in which the lower alkyl group contains from 1 to 4 carbon atoms, unexpectedly and selectively cause 3- keto-4,6-dienic steroids to undergo a 1:6 addition resulting in the formation of the corresponding 3-keto7(a,;5')-loweralkyl-A -steroids. Consequently, there is disclosed herein for the first time a general and readily facile method of preparing the above-identified class of 7(a,fi)-loweralkyl- 3-keto-A -steroids.

Additionally, the compounds of this invention readily undergo acid or base isomerization to the corresponding A steroids. Many of these 7(n p)-loWeralkyl-3-ketoA steroids are well known steroids having recognized valuable biological properties including anabolic, androgenic, estrogenic and other hormonal properties, in addition to the antitumor properties of such clinically valuable compounds as 7a,17a-dimethyltestosteroneterone (T. I. Cantino, E. Eisenburgh and G. S. Gordon, Cancer, 1966, 19, 817) and 7,3,l7a-dimethyltestosterone (G. S. Gordon, A. Holden and R. M. Walter, Clinical Research, 1970, 18, 155). In view of the satisfactory yields obtained in both preparation of the 3 keto-7(an?)-loweralkyl-A -steroids and their conversion to the corresponding 3-keto-7 (41,5)- loweralkyLM-steroids, the procedures described in this invention represent, in general, a preferred route to the preparation of the 7(a,/3) loweralkyl-3-keto-A -class of steroids. These processes can be best illustrated by means of the following generalized reaction schemes:

4] Alkyll I I Isomeration 0 W R ization III IV DETAILED DESCRIPTION OF THE INVENTION The novel 7(c n)-loweralkyl-3-keto-A -steroids are prepared by the reaction of a 3-keto-4,6-dienic steroid with a loweralkylcopperlithium reagent, a loweralkylcoppertrialkylphosphite complex or a loweralkylcoppertrialkylphosphine complex, in which the loweralkyl group contans from 1 to 3 carbon atoms, contained in an inert anhydrous organic solvent. When the addition is performed in ether or tetrahydrofuran the metallic enolate ions of the correspending 7 (a, 8)-loweralkyl-3-hydroxy-3,5-dienic steroids is obtained from which the desired 7 (a,p)-lower-alkyl-3 ketoA -steroids are generated by protonation.

When the symbol R is hydrogen in each of formulas I and II above, the 19-nor androstane and 19-nor pregnane series of compounds are designated. Illustrative of such compounds are 17;; hydroxy-7a-rnethylestra-5-en-3-one and 7a-methyl-19-norpregn-5-en-3,Z-O-dione.

When R represents an u-methyl group in each of the formulas I and II above, the hydrogen in the 9 position must be in the ii-configuration. Illustrative of such compounds are 17,6-hydroxy-7a-methyh9/3,10a-androst-5-en-3- one, -hydroxy-6,7-dimethyl-9B,l0a-androst-5-en-3-one, 7tx-rnethyl-9fi,10a-pregn-5-ene-3,20-dione, 17a hydroxy- 7a-methyl-9/5,10a-pregn-5-ene-3,ZO-dione acetate, and 6,7- dimethyl-9B,10a-pregn-5-ene-3,ZO-dione.

Conversely when R represents a ,B-methyl group, the hydrogen in the 9 position must be in the a: configuration. Illustrative of compounds which fall within this group are 17 fl-hydroxy-7a-methyIandrOst-S-en-3-one and 7a-methylpregn-5-ene3,20dione.

The symbols R and R in formulas I and II can be either hydrogen or methyl. When R is methyl, the methyl group may be in either the at or B configuration, whereas when R is methyl its stereochemistry is fixed by the unsaturation in the A position. Illustrative of such compounds are 17/3-hydroxy-1,7-dimethylandrost-5-en-3-one, 17/8-hydroxy 4,7 dimethylandrost-5-en-3-one, 17,3-hydroxy-6,7,17a-trimethyIandrQst-S-en-3-one, 1a,7a,160t-[rimethylpregn-5-ene-3,ZO-dione, and 17a hydroxy-6,7a-dimethylpregn-5-ene-3,20-dione, acetate.

The alkylation of 3-keto-4,6-dienic steroids in accordance with the process hereinafter described, inserts an alkyl group in the 7-position as is indicated by the symbol R in formulas I and II. In general the process yields a mixture of 7a and 7fi-alkylated steroids having an alkyl group containing from 1 to 3 carbon atoms. The individual pure 7a and 7fi-alkylated compounds may be separated and obtained in pure form via standard fractionation methods. Illustrative of 7-alkyl steroids prepared in this manner are 175 hydroxy-7u-methylandrost-S-en-3- one propionate, 17f3-hydroxy 7/3 methylandrost-S-en-3- one propionate, 175-hydroxy-7p-isopropylandrost-5-en-3- one, 17B-hydroxy-7a-ethylandrost-S-en 3 one, l7fl-hydroxy-7B-ethylandrost-5-en 3 one, 7a-methylpregn-5- ene-3,20-dione, 7B-methylpregn-5-ene-3,ZO-dione, 7tx-ethylpregn-5-ene-3,ZO-dione, and 7[3ethylpregn-5-ene 3,20- dione.

The symbol R represents either hydrogen or an oxo group thus giving rise to the ll-oxo androstane and the ll-oxo pregnane series of compounds. Typical of such compounds are 7u-methylandrost-5-ene 3,11,17 trione, 7a-methyl-estr 5 ene-3,l1,l7-trione, 7ot-methylpregn-5- lane-3,1 1,20-trione, 17u-hydroxy 6,7-dimethylpregn-5-ene 3,11,20-trione and 17a-hydr0xy-7a,16a-dimethylpregn-5- ene-3,1 1,20-trione.

' The expression R in both the androstane and pregnane series can be hydrogen, methyl or ethyl. Typical compounds include 13-ethyl-17fi-hydroxy-7-methylgon-5-en-3- one, acetate, and 1S-ethyl-17a-hydroxy-7a-methyl-18,19- dinorpregn-5-ene-3,ZO-dione, acetate.

The expression R in Formulal is intended to encompass both saturated and unsaturated aliphatic carbon groups containing from 1 to 6 carbon atoms in the alpha position. Illustrative members of this group include 17,8- hydroxy-7a,17a-dirnethylandrost-5 en 3 one, 17,8-hydroxy-7a-methy1-17a-(1 propynyl)-estr-5-en-3-one, and 17,8-hydroxy-7-methyl-17ot-vinylandrost-5-en3-one.

The symbol R in the androstane series is in the beta configuration and represents hydrogen, the hydroxyl group and one of several alicyclic or heterocyclic ethers such as the 1-cyclopenten-1-yl, l-methoxycyclohexyl and Z-tetrahydropyranyl ethers. Additionally, the symbol R encompasses the expression OR in which the symbol R represents an acyl radical having from 1 to 12 carbon atoms. Illustrative of such compounds are 7-methyl-17fl [(tetrahydropyran-2-yl)oxyl-androst-S-en 3 one, 1713- hydroxy-7a-methylandrost-5-en-3 one-butyrate, and 176- hydroxy-h-methylandrost-5-en-3-one hydrocinnamate.

When the symbol R is represented by one of the unsaturated members in the androstane series, such as ethinyl, the symbol R may not be represented by the O-acyl group, i.e., it may only be represented by hydrogen, hydroxyl or one of the enumerated alicylic or heterocyclic ethers. Illustrative of such compounds are 1706- ethinyl-17fi-hydroxy-7a-methyIandrOst-S-en 3 one and 17a-(butyryl)-17,8-hydroxy-Y-methylestr-Sen-3-one.

Alternatively, the symbols R and R in the androstane series can be considered together as representing an oxo radical thereby forming the 3,17-androstanedione series of compounds. Illustrative of such compounds are 7a-methylandrost-5-ene 3,17 dione and 6,7-dimethylandrost-5ene-3,17-dione.

The symbols R and R may also be taken together to form cyclic 17-ethylene acetals or 1,3-dioxolane derivatives of androstane. Typical of such compounds are 7amethylandrost-S-en-S,17-dione cyclic 17-(ethylene acetal) and 7B-methylandrost-5-en-3,17-dione cyclic 17-(ethylene acetal).

In the pregnane series the 16-position may be substituted in either the alpha or beta configuration by the symbol R Which represents hydrogen, methyl or a methylene group. Typical of such 16-substituted compounds are 104,7,16a-trimethylpregn-5-ene-3,2O-dione, 17cc hydroxy- 7,16ot-dimethylpregn-5-ene-3,ZO-dione and 7,16wdimethylpregn-5-ene-3,20-dione.

The symbol R in the pregnane series is in the alpha configuration and represents hydrogen, methyl, ethyl, and the Z-tetrahydropyranyloxy radical. An example of such a compound is 7a-17oi-dimethylpregn-S-ene-3,ZO-dione.

Additionally, the symbol R in the pregnane series encompasses the expression OR wherein the symbol R represents hydrogen, a loweralkyl group having from 1 to 3 carbon atoms and an acyl radical having from 1 to 12 carbon atoms. Illustrative of such compounds are 1704- hydroxy-h-methylpregn-5-ene-3,2O dione, acetate, 17ahydroxy 6,7a dimethylpregn-5-ene-3,20-dione, acetate, and 17a-hydrOXylJu-methyl-pIegn-S-ene-3,20-dione, and 17a-methyloxy-7a-methyIpregn-S-ene-Ei,ZO-dione.

It is to be noted, however, that when the 16-position in the pregnane series is methylene, R may not be represented by the O-acyl radical. In such circumstances, R may only be hydrogen, hydroxy, methyl, ethyl, Z-tetrahydropyranyloxy and the loweralkyl ethers. Illustrative of such compounds are 17a-rnethoxy-7a-methyl-16-methylenepregn-5-ene-3,ZO-dione, and l7og-methoxy-6,7a-dimethyll 6-methylenepregn-5 -ene-3 ,20-dione.

When the symbols R and R are taken together in the pregnane series, the 16a,17otalkylidenedioxy derivatives are formed. The preferred compounds among this class of steroids are 16a,17u-dihydroxy-7wmethylpregn-5- ene-3,20-dione, cyclic acetonide with acetone and 16a, 17a dihydroxy-6,7a-dimethylpregn-S-ene 3,20 dione, cyclic acetonide with acetone.

The symbol R in the pregnane series can be hydrogen, the hydroxyl group and one of several alicyclic or heterocyclic ethers such as the l-cyclopenten-l-yl, l-methoxycyclohexyl and Z-tetrahydropyranyl ethers. The symbol R may also represent the expression OR in which R represents an acyl radical having from 1 to 12 carbon atoms. Examples of such pregnanes include 2OB-hydroxy- 7ot-methy1-9B,10u-pregn-5-en 3 one, 205-hydroXy-7w methyl 93,1004 pregn-5-en-3-one, acetate and ZOB-hydroxy-7ot-methylpregn-5-en-3-one.

Although the C-20 position appears to include both mono and di-substituted derivatives, the present invention intends to encompass only the mono-substituted derivatives at this position. Accordingly there must always be hydrogen at the C-20 position. The exception to this general rule occurs when both the R and R groups are taken together to represent an oxo group giving rise to the 3,20-pregnadione derivatives as for example 704 methylpregn-5-ene-3,20-dione.

The process of the present invention is generally applicable and may be applied to a large variety of steroidal 3 keto-4,6-dienese which are derived from such basic steroidal ring systems as androstane, 19-nor-androstane, pregnane, 19-norpregnane and to modifications as represented by the 18-methyl homologues, 18-ethyl homologues and the D-homo homologues. Additionally the process of this invention may be applied to the 9,3:10u-steroisomers of the aforementioned androstane and pregnane ring systerns.

Thus, in the androstrane series the 3-keto-7(a,,8)-loweralkyl-A -androstanes are conveniently prepared in good yield by reacting a diloweralkyllthium cuprate or other organocopper reagent such as a loweralkylcopper complexed with trialkylphosphites or a loweralkylcopper complexed with trialkylphosphines in which the loweralkyl group contains from 1 to 3 carbon atoms, with a 3-keto- 4,6-androstadiene substrate having the general formula:

wherein the various R groups have the meanings hereinbefore assigned. In general the starting materials are known compounds which can be made by methods described in the literature, e.g., Zderick, et al., JACS, 80, 2596 (1958) and H. J. Ringold and A. Turner, Chem. Ind., 211 (1962).

Similarly, in the pregnane series, the 3-keto-7(u,{3)- loweralkyl-M-pregnanes are also conveniently prepared and in good yield by reacting a diloweralkyllithium cuprate or a loweralkylcopper complexed with trialkylphosphites or a loweralkylcopper complexed with trialkyl phosphines, in which the loweralkyl group contains from 1 to 3 carbon atoms, with a 3-keto-4,6-pregnadiene having the general formula:

wherein the various R groups have the meanings hereinbefore assigned.

The organocopper reagents described and utilized in the present invention are highly specific in that they will selectively alkylate the 7-position of a 3-keto-4,6-dienic steroid via a 1:6 addition reaction. These reagents fall within three clases of organocopper compounds: diloweralkyllithium cuprates, a loweralkylcopper complexed with a trialkylphosphite, and a loweralkyl copper complexed with a trialkylphosphine, where the alkyl and loweralkyl groups contain from 1 to 3 carbon atoms. The diloweralkyllithium cuprates are the preferred reagents in carrying out the alkylation reaction with dimethyllithium cuprate representing the preferred species. However, the remaining classes of organocopper reagents will also undergo the conjugate addition reaction with the methylcopper complex of tri-n-butylphosphine being particularly eifective.

The diloweralkyllithium cuprate reagents are conveniently prepared from an ethereal solution of loweralkyllithium and cuprous iodide in the molecular ratio of 221 under N at a temperature of from about C. to about 78 C., as reported by H. 0. House, W. L. Respess and G. M. Whitesides, J. Organic Chemistry 1966, 31, 3138. In addition to the use of diethyl ether as a solvent the reagent may be prepared in other inert anhydrous organic solvents. By the term anhydrous solvent is meant any nonaqueous solvent which is non-reactive to the organocopper reagent in which the reagent is soluble. Thus, for example, petroleum ether, tetrahydrofuran, hexane or mixtures of these solvents are suitable solvents for the organocopper reagent.

The molar proportion of the diloweralkylcopperlithium reagent necessary to insure completeness of the reaction is dependent upon the substrate employed. A minimum of 2 moles of diloweralkylcopper lithium is necessary per mole of substrate in order for the 1:6 addition reaction to take place. One additional molar ratio of diloweralkylcopperlithium is required for each other substituent of the substrate susceptible to metallation by the reagent, as for example, a hydroxyl group.

The 1:6 addition reaction can be carried out at temperatures ranging from about 100 C. to about -78 C. Temperatures below ambient temperatures are preferably employed. The specific temperature will vary with the organometallic reagent employed and the nature of the steroid substrate. Thus, for example, when dimethylcopperlithium is employed, a reaction temperature of 0 C. is snfiicient to insure rapid addition. When diisopropylcopperlithium is employed as a reagent, a lower temperature is necessary since this particular or-ganometallic reagent is unstable at room and elevated temperatures. A convenient temperature in which to operate is C.

The organometallic reagent adds rapidly to the steroid substrate with the formation of the metallic enolate ions derived from the corresponding 7(u,,6)-loweralkyl-3-hydroxy-3,5-dienic structures. The preferred method of reacting the steroid substrate is to dissolve or suspend the steroid substrate in an inert anhydrous organic solvent and add the resulting solution or suspension to the organocopper reagent dissolved in an inert anhydrous organic solvent. A reverse addition may also be utilized. The addition reaction takes place rapidly, with the reaction time being essentially controlled by the rate of addition. A preferred method of control is via the dropwise addition of a solution of the steroid substrate to a solution or suspension of the organocopper reagent. In certain instances, as for example when reacting large quantities of material, it may be desirable to stir the reaction mixture for a period of several hours thereafter.

Following the addition of the organometallic reagent the reaction mixture is quenched by the addition of a protonating agent such as a saturated solution of ammonium chloride, oxalic acid or boric acid. Generally, mixtures of 70a and 7 fi-loweralkyl-M-steroids are obtained which can be separated by standard procedures such as fractional crystallization and chromatographic separation.

This reaction is highly specific in alkylating the 7-position, notwithstanding a large variety of substituents which may already be present on the steroid nucleus. Consequently this reaction is useful in alkylating steroids having other active site centers without the need for providing protecting groups for such centers. Illustrative of the various substituents which remain unaffected by the alkylating process are:

(1) unconjugated carbonyl functions in the 11, 12, 15, 16, 17 and 20 positions which remain unafiected inasmuch as the organometallic reagent reacts only slowly with such carbonyl groups;

(2) hydroxyl groups in the 16, 17 and 20 positions, although metallated by the reagent, are regenerated during the protonation of the reaction mixture;

(3) acyloxy groups in any position remain generally unalfected;

(4) ether groups exemplified by the following partial structures remain unafiected;

Ro I

(5) lower alkyl groups, particularly methyl groups,

which may be present in such positions of the steroid nucleus as 1, 2, 4, 6, 11,12, 15, 16, i7, 18, 20 and 21, and ethyl groups in such positions as 16, 17, 18 and 20, are not afiected;

(6) methylene and cyclomethylene groups in the 16, 17, 18 and 2 0 positions remain unaltered so long as the methylene groups do not contain vicinal acyloxy or 0x0 functions;

(7) unsaturated aliphatic carbon residues containing up to 6 carbon atoms, including both double and triple bonded systems, remain unafiected providing they do not contain any acyloxy or oxo functions vicinal to their unsaturation; and

(8) a spironolactone side chain in the 17-position generally remains unaffected by this reagent.

As previously indicated, 3-keto-7(a,fl) -loweralkyl-A steroids produced in accordance with the present invention are readily isomerized to their corresponding A counterparts, by treatment with an acid or base in an appropriate solvent. Thus, 3-keto-7 (a,,6)-1oweralkyl-A androstanes having the general formula:

wherein the various R groups have the meanings hereinbefore assigned, may be readily prepared from the corresponding 3-keto-7(01, 8)-loweralkyl-A -androstanes shown in formula I.

Similarly, 3-keto-7 (one)-loweralkyl-A -pregnanes having the general formula:

Ra Ra wherein the various R groups have the meanings previously designated, are readily prepared from their corresponding 3-keto-7(0 p)-loweralkyl-A -pregnanes shown in formula II.

Solvents which may be suitably employed include aqueous alcohols, acetic acid, acetone, and chloroform. Aqueous ethanol and acetic acid represent the solvents of choice for the isomerization because of their ready accessibility and ease of removal. In general any readily available acid or base can be used to effect isomerization such as hydrochloric, hydrobromic, sulfuric, phosphoric and acetic acid. Examples of suitable bases include sodium hydroxide, ammonium hydroxide and sodium carbonate.

The isomerization takes place with great facility at temperatures ranging from abient temperature to the boiling point of the solvent used. The conditions are not deemed to be critical, and for the majority of compounds isomerization appears reasonably complete in about one hour. The isolation of the resulting 3-keto-7(a,B)-loweralkyl- M-steroids takes place by any of several methods known to the art. The aqueous organic solvent may be concentrated or removed completely to precipitate the 3-keto- 7(e43)-loweralkyl-A -steroid, which may then be purified by recrystallization. Alternatively the product may be chromatographically purified.

The 3 keto-7 (1x48)-loweralkyl-androstane derivatives illustrated in formula I, wherein R R and R are hydrogen, have anabolic and androgenic activity. Particularly useful are the corresponding 7a-methyl derivatives. Where R R R and R are hydrogen the compounds are useful as anti-fertility agents. These compounds affect the fertility in male and female mammals by a variety of mechanisms depending upon such parameters as species, dosage and time of administration. Thus they fall into the class of claudogenic steroids as described by V. Petrow in J. Pharm. PharmacoL, 12, 7-04 (1960). Additionally, certain claudogenic steroids show both progestational and antiprogestational activity. The presence of methyl substituents at the C C and C positions does not qualitatively alter the biological properties of the parent compounds.

The 3-keto-7(a,;8)-loweralkyl androstane derivatives, particularly the 7et-methyl-17a-substituted androstanes of formula I wherein R R and R is hydrogen and R is not hydrogen, qualitatively resemble the foregoing group of structures in their biological properties. Structures in which R is alkynyl or alkadinyl have progestational activity also evidenced by their corresponding C C C and C methyl derivatives. Such compounds are useful in place of known progestagens for progestagen therapy, e.g., "Progestagen Therapy by Maxwell Roland, American Lecture Series, Publication No. 626, Charles C. Thomas, Springfield, Ill., U.S.A. for the control of fertility in male and female birds and mammals as well as for the treatment of prostatic hypertrophy in the male. The C methyl derivatives can also be isomerized to the corresponding 6,7 (11,13)-dialkylated-A -steroidal ketones which are also useful in the treatment of prostatic hypertrophy in the male. The 3-keto-7(a, S)-loweralkyl-pregnane derivatives illustrated in formula II, particularly the 7a-methyl derivatives, in which R is as previously defined and R is hydrogen or O-acetyl, show progestational activity.

The 7 (0 8) -alkyl and in particular the 7ot-methyl derivatives of structure II where where R R R and R are as hereinabove defined and R is particularly OAc, are distinguished by their progestational properties. These properties are also present in the corresponding C C C and C methyl and C -C methylene derivatives as well as in their ll-oxo derivatives. The 6,7-(a, 8)-dimethyl-A 3-steroidal ketones are particularly useful in the treatment of prostatic hypertrophy in the mole.

The compounds of the present invention are preferably administered in unit dosage forms such as tablets, capsules, powders, granules, sterile solution or suspensions for parenteral use, and oral solutions or suspensions, and cream, lotions or ointments for topical use. Additionally the active ingredients may be administered in sublingual and intrabuccal preparations, formulations for inhalation therapy and insufllation such as sprays and aerosols, intravaginal and rectal suppositories, vaginal rings impregnated with the active ingredients, intrauterine devices and subcutaneous and intramuscular implants or depot preparations.

The dosage of the active ingredient to be administered will depend upon such factors as route of administration, age, weight and the nature of the patients condition being treated or alleviated. A dosage of the therapeutic steroid will generally range from about 0.1 mg. to about 3.0 gm. per administration with repeated dosages ranging from about one to four times daily to once every three months. Illustrative dosage levels for progestagen therapy range from about 0.25 mg. to about 1.5 gm. per single adminstration per patient. In the treatment of prostatic hypertrophy in the male, a daily dosage of the active ingredient will generally range from about 0.25 mg. to 1.5 gm. per single administration per patient. Where the steroid is being administered with one or more active ingredients, the dosage is to be determined with reference to the usual dosage of such ingredients.

For oral administration either solid or liquid dosage unit forms can be prepared. In preparing solid compositions such as tablets, the principal active ingredient is mixed with conventional pharmaceutical excipients such as gelatin, starches, lactose, magnesium stearate, talc, acacia, dicalcium phosphate and functionally similar material. The tablets may be laminated, coated, or otherwise compounded to provide prolonged or delayed action or to release a predetermined succession action of medication. Capsules, like tablets, are prepared by mixing the steroid with an inert pharmaceutical filler or diluent and filled in either hard gelatin capsules or machine encapsulated in soft gelatin capsules.

Liquid dosage forms for oral administration such as syrups, suspensions and elixirs may also be employed. The water soluble forms of the novel steroids of this invention can be dissolved in an aqueous vehicle together with flavoring agents and preservatives to form a syrup. An elixir utilizes a hydro-alcoholic vehicle such as ethanol with suitable sweeteners and flavoring agents. Suspensions of the insoluble forms of the active steroids may be prepared in a suitable syrup vehicle with the aid of suspending agents such as acacia, tragacanth and methyl-cellulose.

The quantity of active ingredient contained in each dosage unit form will, of course, vary with the type of dosage unit and the nature of the condition being treated. Thus it is possible for each dosage unit to contain from about 0.1 mg. to about 3.0 gm. of active ingredient in addition to the non-toxic pharmaceutical excipient contained therein. A preferred range of active ingredient for an orally administered dosage form such as a tablet, cap- :1 1 sule or liquid syrup or suspension ranges from about 50mg. to about 500 mg. of active ingredient per administered dosage.

Parenteral fluid dosage forms are prepared by utilizing; the active ingredient in a sterile liquid vehicle, water or saline solution being the preferred vehicle. The active ingredient can either be dissolved or suspended in the vehicle, generally depending on the form of administration and the concentration used. A water soluble form of the active ingredient can be dissolved in the vehicle and filter sterilized prior to filling a suitable vial or ampule. Alternatively the vial or ampuie may be filled and subsequently sterilized. Adjuvants such as local anesthetics, preservatives and buttering agents can also be added. In order to further enhance stability, the composition may be frozen after filling and the water removed by freeze drying techniques well known in the art. Such dry lyophilized powders are then reconstituted prior to use.

Parenteral preparations including suspensions of micro nized materials, oil suspensions, solutions or suspensions of the active steroid ingredient in biologically degradable materials such as polylactide are also contemplated to be within the preview of the present invention.

Parenteral preparations including suspensions of micronized materials, oil suspensions, solutions or suspensions sterilization cannot be accomplished by filtration. Surfactants or wetting agents are conveniently employed to facilitate uniform distribution of the steroid in the vehicle. A preferred range of the active ingredient for a parenteral fluid dosage form is from about 50 mg. to 3 gm. per administered dose.

Topical ointments can be prepared by dispensing the active ingredient in a suitable ointment base such as petrolatum, lanolin, polyethylene glycols or mixtures thereof. Generally the steroid is finely divided by milling or grinding in a light liquid petrolatum base. Creams and lotions are prepared by dispersing the active ingredient in an oily phase and forming an emulsion therefrom.

The following preparations and examples are illustrative of the products, processes and compositions of the present invention but are not to be construed as necessarily limiting the scope thereof.

EXAMPLE I l713-Hydroxy-7a-methylandrost-5-en-3-one A solution of 141 g. (0.5 mole) testosterone in 750 ml. dioxane was saturated with gaseous HCl and cooled to C. To this solution was added over 20 min. with continuous cooling a solution of 114 g. (0.5 mole) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 750 ml. dioxane saturated with gaseous HCl. The cooling bath was removed and stirring continued an additional 30 min. The reaction mixture was filtered and the solvent volatilized to give a yellow solid. Recrystallization from acetone gave 110 g. of 17fi-hydroxy-androsta-4,6-dien-3-one having a m.p. ZOO-202 C.

A solution of lithium dimethylcopper was prepared under nitrogen by adding 625 ml. of 1.6 M (1 mole) ethereal methyllithium to a slurry of 96 g. (0.5 mole) cuprous iodide in 500 ml. of anhydrous ether at 0 C. This solution was stirred at 0 C. for an additional 10 min. followed by the dropwise addition of a solution of 30 g. (0.1) 17B-hydroxyandrosta-4,6-dien-3-one in 500 ml. of anhydrous tetrahydrofuran. The reaction mixture was stirred for an additional 30 min. at 0 C. and then poured into 2 liters of a saturated aqueous ammonium chloride solution. Benzene was added and the mixture was filtered rapidly through diatomaceous earth. The benzene layerwas washed with saturated aqueous ammonium chloride, with water, and dried (MgSO Evaporation of the solvent gave a solid which was covered with acetone and filtered. Recrystallization from acetone gave 10 g. of the desired l7B-hydroxy-7a-methylandrost- 5-en-3-one; m.p. 200-216" C.; UV'max. (EtOI-I) 288 12 nm. (e 82); IR (KBr) 1700 cm? (0:0); 'NMR (CDCI 6 5.37 (m, C-6 H), 0.81 (d, C-7 CH J.:Hz.). Analysis.Calcd for 0201 13002: C, H, Found: C, 79.58; H, 10.10. In accordancewith theabove procedure, but substituting for the 17fi-hydroxyandrosta-4,6-diene3-one I an, equivalent amount of:

Androsta-4,6-diene-3one. l7fi-hydroxy-1a-methylandrosta-4,6-diene-3-one, 17,6-hydroxy-4-methylandrosta-4,6-diene-3-0ne, and 1718-hydroxy-4-methylandrosta-4,6diene-3-one-acetate. the following compounds were respectively obtained: 7-methylandrosta-S-en-3-one,

l 7,8-hydroxy-10:,7-dimethylandrost5-en-3-one, 17 B-hydroxy-4,7-dimethylandrost-5-er1-3-one, and 175-11ydroxy4,7-dimethylandrost-5-en-3-one, acetate.

EXAMPLE II 17B-Hydroxy-7 a-methylandrost5-en-3-one Methyl copper was prepared under nitrogen by adding 94 ml. of 1.6 M (0.15 mole) ethereal methyllithlum to an ice-cold (0 C.) slurry of 28.56g. (0.15 mole) cuprous' iodide in 800 ml. anhydrous ether. The yellow suspension was converted to a black solution of methylcopper-trimethylphosphite complex by the addition of 55.8 g. (0.45 mole) trimethylphosphite. Immediately thereafter 14.3 g. (0.05 mole) of l7fi-hydroxy-androsta-4,6-dien3; one in 150 ml. of anhydrous tetrahydrofuran was added dropwise and stirring continued for min. at 0 C. The reaction mixture was poured into 1 liter of saturated aqueous ammonium chloride. Benzene was added and the mixture rapidly filtered through diatomaceous earth. The benzene layer was washed once with saturated aqueous ammonium chloride, with water, and dried over magnesium sulfate. The solution was filtered and concentrated under a vacuum. The residue remaining was crystallized from acetone to give 2 g. of the desired 17 3-hydroxy-7a- EXAMPLE III Isomerization of 17p-hydroxy-7u-methylandrost-S-en-B- one to 17/3-hydroxy17u-rnethylandrost-4-en-3-one 17fi-hydroxy-7a methylandrost-S-en-3-one was dissolved in methanol at room temperature and HCl gas bubbled through the solution for 1 minute. The solvent was evaporated and the remaining residue recrystallized from an acetone-hexane solution to give the'corresponding l7,6-hydroxy-7ot-methylandrost-4-en-3-one.

l7B-hydroxy-7or-methylandrost 5-en-3-one was also isomerized under alkaline conditions. The compound was dissolved in methanol at room temperature and sodium methoxideadded. The solution was stirred for 30 minutes and the resulting solution was poured into an ice-water mixture and extracted with ether. The ether extract was washed with water, dried over magnesium sulfate and concentrated. Recrystallization of the residue from acetone-hexane gave 17fl-hydroxy-7ot-methylandrost-4-en 3-one. EXAMPLE 1V 7a-methyl-l7B-hydroxyandrost-S-en-3-one acetate 73- methyl-17B-hydroxyandrost-5-en-3 one acetate A solution of g. (0.152 mole) testosterone acetate in 500 cc. dioxane was saturated with gaseous HCl and added all at once to a solution of 34.5 g. (0.152 mole) of 2,3-dichloro-5,6-dicyano-1.4-benzoquinone in 500 ml. dioxane saturated with gaseous HCl. The reaction mixture was stirred at room temperature for 5 minutes and filtered. Evaporation of the solvent gave a brown solid which was passed through a short alumina packed column and eluated with acetone until the colored band reachedthe base of the column. The combined eluant was recrystallized from acetone-hexane solution to give 40 g. 1713- acetoxy-androsta-4,6-dien-3-one: m.p. 141-142" C.

"-A solution of lithium dimethyl copper was prepared under nitrogen by adding 10 ml. of 1.6 M (0.160 mole) ethereal methyllithium solution to a slury of 16.7 g. (0.88 mole) 'cuprous iodide contained in 100 ml. anhydrous ether at C. The solution was maintained at 0 'C. for'an additional minutes and a solution of g. (0.03 mole) 17 8-acetoxyandrosta-4,6-dien-3-one in 50 ml. anhydrous tetrahydrofuran was added over a 1 minute period. The mixture was stirred an additional 2 minutes and poured into a saturated aqueous ammonium chloride solution. Benzene was added and the mixture rapidly'filtered through diatomaceous earth. The organic layer was washed with saturated aqueous ammonium chloride, followed by a water wash, dried over magnesium sulfate and evaporated. The resulting 'oil was dissolved in methylene chloride and rapidly chromatographed through a silica gel column packed with methylene chloride. The material which eluted with the sol-vent front was recrystallized twice from hexane to give the desired 7a-methyl-17B- hydroxyandrost-5-en-3-one acetate: m.p. 142-155 C.; UV max. (EtOH) nm. (sh); IR (KBr) 1710-1730 cm." (C=O)-ester C:O); NMR (CD1 5 5.37 (m, C-6 H), 0.81 (d, C7 CH- J=7 Hz.).

Analysis.Ca-lcd for C H O C, 76.70; H, 9.36.

Found: C, 76.59: H, 9.49.

The combined mother liquors were evaporated and the resulting oil recrystallized from pentane. This solid was thenuechromatographed on a silica gel column packed in methylene chloride. The solid eluant was 7fl-methyl-l75- hydroxy-androst-S-en-3-one acetate: m.p. 100-107 C.; UV maX.- (EtOH) 236 nm. (sh); IR (KBr) 1710 (0:0), 1725 cm. (ester C=O); NMR (CDCl 6 5.12 (broad t, 6-6 H), 0.98 (d, C-7 CH J 7 Hz.).

Analysis.Calcd for C H O C. 76.70; H, 9.36. Found: C, 76.83; H, 9.46.

Following this procedure but substituting for 1713- acetoxyandrosta 4,6"- dien 3 one the appropriate equivalent amounts off" l75-hydroxyandrosta-4,6-dien-3-one, butyrate, 17fi-hydroxyandrosta-4,6-dien-3-one, benzoate, '17 S-hydroxy 1 7 a-rnethylandrostat,6-dien-3-one, acetate,

175-hydroxy-1-7a-methylandrosta-4,6-diene-3 ,1 l-dione,

- acetate, and

17B-hydroxy-1ot-methylandrosta-4,6-dien-3-one, acetate,

the following substituted 17/8-hydroxy-androst-5-ene-3 ones were respectively obtained: 17fi-hydroxy-7-methylandrost-5-en-3-one, butyrate, 17,6-hydroxy-7-methylandrost-S-en-3-one, benzoate, l7Bhydroxy-7,17tx-dimethylandrost-iren-3one, acetate, 17/3-hydroxy-7, l 7u-dimethylandrost-5-ene-3 ,1 l-dione,

acetate, and 1 1 17,8-hydroxy-1a,7 dimethylandrost-5-en-3-one, acetate.

. EXAMPLE V 17,8 hydroxy 7a methylandrost 5 en 3 one i I propionate 173 hydroxy 7B methylandrost .5 enjj3-one propio'nate solution of 30 g. 17/3-hydroxyandrosta-4,6-dien-3-one in 180ml. pyridine and 180 m1. propionic anhydride were left at room temperature-for 18 hours. The solution was poured intowater-and the solidfiltered and recrystallized from acetone-hexane to give 27:6 g. of 17,6 hydroxyandrosta 4,6 dien 3 one propionate having a mp 134-136 C.

I A solution of lithium dirnethylcopper was prepared under .nitrogen 'by adding 262ml. of 16. M (0.42 mole) etherealmethyllithium to a slurry of 45.7 g. (0.24 mole) cuprous iodide in 300 ml. anhydrous ether at 0 C. The solution was maintained at 0 C. for an additional minutes and drama solution of 27.6 g. (0.081 mole) 17B- hydroxyandrosta 4,6 dien 3 one propionate in 100 ml. anhydrous tetrahydrofuran was added over a period of two minutes. The mixture was stirred for an additional one minute and poured into a saturated aqueous ammonium chloride solution. Benzene was added and the mixture rapidly filtered through diatomaceous earth. The organic layer was washed with a saturated aqueous ammonium chloride solution, then with water, dried over magnesium sulfate and evaporated to dryness. The resulting oil was dissolved in methylene chloride and rapidly chromatographed through a silica gel column packed in methylene chloride. The material which eluted with the solvent front was recrystallized from hexane to give the desired 17;? hydroxy 7,8 methylandrost 5 en 3- one propionate: mp 144-148 C.; UV max. (EtOH) 242 nm. (sh); IR (KBr) 1730 (ester C=O),,l710 cm? (C=O); NMR (CDCl 6 5.1 (broad t, C-6H), 0.97 (d, C7 CH i=7 Hz.).

Analysis.Calcd for C H O C, 77.05; H, 9.55. Found: C, 77.14; H, 9.61.

The mother liquor was evaporated and the resulting oil rechromatographed on a silica gel column packed in methylene chloride. The semi-solid mass was layered with pentane and filtered. The pentane solution was concentrated and on standing 17B hydroxy 7oz methylandrost- S-en-3-one propionate precipitated: mp 82-85 C.; UV max. (EtOH) 244 nm. (sh); IR (KBr) 1725 (ester 0:0), 1710 cmr (C=O); NMR (CDCl 6 5.37 (111, C-6 H), 0.81 (d, C-7 CH J=7 Hz.).

Analysis.-Calcd for C H O C, 77.05; H, 9.55. Found: C, 77.18; H, 9.64.

Following the above procedure of Example V and sub stituting for 17B-hydroxyandrosta 4,6 dien 3 one propionate an equivalent amount of 17/3-hydroxy-17tx-methylandrosta-4,6-dien-3-one,

propionate,

17fi-hydroxyandrosta-4,6-dien-3-one, phenoxyacetate 17fl-hydroxyandrosta-4,6-dien-3-one, hydrocinnamate and 17,8-hydroxy-1ot-methylandrosta-4,6-dien-3-one,

propionate,

the following compounds were respectively obtained:

EXAMPLE VI 7a-methylandrost-5-en-3,17-dione A solution of 22.7 g. (0.1 mole) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 250 ml. of dioxane saturated with gaseous HCl was added all at once to a solution of 28.6 g. (0.1 mole) of androstenedione in a solution of 500 ml. of dioxane saturated with gaseous HCl. The reaction mixture was stirred for 30 minutes at room temperature and filtered. The dioxane solution was evaporated and the residue recrystallized from acetone-hexane to give 28 g. of androsta 4,6 dien 3,17 dione having a mp of 163l66 C.

A solution of lithium dimethylcopper was prepared under nitrogen by adding 156 ml. of 1.6 M (0.25 mole) ethereal methyllithium to a slurry of 24 g. (0.126 mole) cuprious iodide contained in ml. of anhydrous ether at 0 C. A solution of 14.2 g. (0.05 mole) of androsta- 4,6 dien 3,17 dione in 150 ml. anhydrous tetrahydrofuran was added and the reaction mixture stirred at 0 C. for 3 minutes. The mixture was poured into 1.5 liters of a saturated aqueous ammonium chloride solution, diluted with benzene and rapidly filtered through diatomaceous earth. The benzene layer was washed with a saturated solution of aqueous ammonium chloride, then water, dried with MgSQz, and concentrated to an oil. The oil was dissolved in methylene chloride and chromatographed on a silica gel column packed in methylene chloride. The methylene chloride eluauts were combined and recrystallized three times from acetone, once from methylene chloride, and finally triturated with ether. The ether mixture was filtered and concentrated to give the desired 7zx-methy1- androst 5 en 3,17 dione: mp 170-185 C., UV max. (EtDI-I) 242 (sh) nm., 290 nm. (e 115); IR (KBr) 1710, 1695 cm." (C=); NMR (CDCI a 5.4 (In, (3-6 H), 0.85 (d, C-7 CH J=7 Hz.).

Analysis.Calcd for C H O C, 79.96; H, 9.39. Found: C, 79.89, 79.69; H, 9.54, 9.38.

EXAMPLE VII 17 B-hydroxy-7a-17a-dimethylandrost-5 -en-3-one A solution of 12 g. (0.05 mole) of 2,3-dichloro-6,6 dicyano 1,4 benzoquinone in 200 ml. dioxane saturated with gaseous HCl was added all at once to 0 C. solution of i5 g. (0.05 mole) of flat-methyl testosterone in 500 m1. of dioxane saturated with gaseous HCl. The reaction mixture was stirred for 30 minutes at room temperature and filtered. The dioxane was removed under vacuum and the residue recrystallized twice from acetonehexane to give g. of 1713 hydroxy 7a methylandrosta-4,6-dien-3-one: mp 190-195 C.

A solution of lithium dimethylcopper was prepared under nitrogen by adding 188 ml. of 1.6 M (0.3 mole) ethereal methyllithium to a slurry of 28.5 g. (0.15 mole) of cuprous iodide in 200 ml. of anhydrous ether at 0 C. A solution of 9.0 g. (0.03 mole) of I'Tfi-hYdIOXY-l'l'a-Hlfithylandrosta-4,6-dien-3-one in 200 ml. of anhydrous tetrahydrofuran was added dropwise. The reaction mixture was stirred at 0 C. for 30 minutes and poured into 750 ml. of a saturated aqueous ammonium chloride solutron. Benzene was added and the mixture was filtered through a bed of diatomaceous earth. The benzene layer was washed with a saturated aqueous ammonium chloride solution, with water, dried over MgSO, and evaporated under vacuum. The resulting oil was recrystallized three times from ether to give the desired l7fi-hydroxy- 7a,17a-dimethylandrost-5-en-3-one: mp 159-179 C., UV max. (EtOH) 235 nm. (sh); IR (KBr) 1700 cm? (C: 0); NMR (CDCl 6 5.36 (111, C-6 H), 0.80 (d, C-7 CH J=7 Hz.).

Anal. Calcd for C H O C, 79.70; H, 10.19. Found: C, 79.70; H, 10.23.

EXAMPLE VI=II 17 a-ethinyl-17 3-hydroxy-7-methylandrost-5 -en-3-one A solution of 50 g. (0.16 mole) of 17u-ethinyl testosterone in 500 ml. dioxane was saturated with gaseous HCl and added to a solution of 36 g. (0.16) of 2,3-dichloro 5,6-dicyano-1,4-benzoquinone in 250 ml. of a dioxane solution saturated with gaseous HCl. The reaction mixture was stirred for 30 minutes at room temperature and filtered. The filtrate was concentrated to 250 ml., chilled, and filtered to give 42 g. of 17a-ethinyl-17B-hydroxyandrosta-4,6-dien-3-one: mp 259263 C.

A solution of lithium dimethylcopper was prepared under nitrogen by adding 406 -ml. of 1.6 M (0.65 mole) ethereal methyllithium to a slurry of 64 g. (0.335 mole) of cuprous iodide suspended in 300 ml. of anhydrous ether at 0 C. To the solution was added a solution of 20 g. (0.065 mole) of 17a-ethinyl-l7 8-hydroxyandrosta- 4,6-dien-3-one in 750 ml. of anhydrous tetrahydrofuran over a 20 minute period. The reaction mixture was stirred for an additional 30 minutes at 0 C. and then poured into 1 liter of a saturated aqueous ammonium chloride solution. Benzene was added and the mixture filtered through diatomaceous earth. The organic layer was washed with a saturated solution of aqueous ammonium chloride, dried over sodium sulfate and evaporated to dryness. The dark residue was dissolved in methylene chloride and rapidly chromatographed through a 400 g. silica gel column packed in methylene chloride. The

solid eluant was recrystallized twice from acetone-hexane mixture to give the desired 17a-ethiny-l7 8-hydroxy-7- methylandrost-5-en-3-onez mp 170-172" 0.; UV max. (EtOH) 240 nm. (sh); IR (CHCl 1700 cm." (C=O) NMR (CDCI 6 5.37 (m, C-6 H), 5.1 (m, C-6 H), 0.98 (d, C-7 flCH 1:7 Hz.), 0.83 (d, C-7 aCH J=7 Hz.).

AnaL-Calcd for C H O C, 80.94; H, 9.26.'Found: C, 80.83; H, 9.27. 1

Following this procedure but substituting for the 170:- ethinyl 17fl-hydroxyandrosta-4,6-dien 3 one equivalent amounts of 17B-hydroxy-17a- 1- 3-hydroxypropynyl) androsta 4,6-dien-3-one and l7fi-hydroxy 17a-vinylandrosta 4,6-dien-3-one, resulted in the formation of: 1718- hydroxy 17u-[1-(3-hydroxypropynyl)] 7 methylandrost-5-en-3-one and 17/3-hydroxy 7-methyl 17a-vinylandrost-5-en-3-one, respectively.

EXAMPLE IX 7ot-methylandrost-5-en-3,17-dione cyclic 17-(ethy1ene acetal) 7fi-methylandrost-5-en-3,17-dione cyclic 17- (ethylene acetal) 27 g. of pyridinium hydrobromide perbromide was added in small portions to a solution of 20 g. of 3/8-hydroxy-androst-S-ene-l7-one cyclic ethylene ketal in 250 ml. pyridine at 0 C. The reaction mixture was maintained at 0 C. for 3 hours and then stirred at room temperature for an additional 2 hours. After recooling to 0 C. a solution of 15 g. of chromium trioxide in 150 ml. pyridine was added slowly. Stirring was continued for an additional 3 hours at 0 C. The reaction mixture was stirred at room temperature overnight, poured into water and extracted with benzene. The benzene extract was Washed with water, dried over MgSO, and evaporated. The residue was dissolved in 360 ml. of dimethylformamide and 36 g. of lithium chloride and 36 g. of lithium carbonate were added. This reaction mixture was heated on a steam bath for 30 minutes, allowed to stand at room temperature for an additional 2 hours, filtered, concentrated to ml., diluted with water, andextracted with methylene chloride. The methylene chloride extract was dissolved in benzene, placed on an alumina column packed in benzene, and eluted with benzene. Recrystallization of the eluant from an ether-pentane mixture yielded 12 g. of androsta-4,6-dien-3,17-dione, cyclic 17-(ethylene acetal) having a mp 152-157" C.

A solution of lithium dimethylcopper wasprepared under nitrogen by adding 188 ml. of 1.6 M (0.3 moles) of an etheral methyllithium solution to a slurry of 29 g. (0.15 mole) of cuprous iodide suspended in 200 ml. anhydrous ether at 0 C. The solution was stirred an additional 10 minutes at 0 C. and a solution of 10.9 (0.033 mole) of androst-4,6-dien-3,17 dione cyclic 17- (ethylene acetal) in 150 ml. of anhydrous tetrahydrofuran was added over a period of 15 minutes with continuous stirring at a temperature of 0 C. Stirring was continued for an additional 30 minutes at 0 C., the mixture poured into 1 liter of a saturated aqueous ammonium chloride solution, benzene added and the resultant mixture rapidly filtered through diatomaceous earth. The organic layer was washed with a saturated aqueous ammoniumchloride solution, washed with water, dried over MgSO and concentrated to an oil. The oil was dissolved in methylene chloride and rapidly chromatographed on a silica gel column packed in methylene chloride. The methylene chloride containing eluant was crystallized four times from ether-pentane solution to give the desired 7a-methylandrost-5-en-3,17-dione, cyclic l7-(ethyleneacetal): mp 141 C., UV max. (EtOH) 240 nm (sh); IR'(-KBr) 1700 cm.- (C=O); NMR (CDCl 6 5.39 (In, C-6" H),

0.83 (d, C-7 CH J=7 Hz.).

Anal.Calcd for C H O C, 76.70; H, 9.36. Found:

The combined mother liquors were treated with etherpentane solutions. The solid was filtered and the mother liquor concentrated to an oil. This oil was recrystallized twice from hexane to give the desired 7,8-methylandrost- 5-en-3,17-dione, cyclic 17-(ethylene acetal): mp 106- 116 C., UV max. (EtOH) 237 nm. (sh); IR (KBr) 1700 cm.- (C=O); NMR (CDCl 6 5.12 (broad t, C-6 H), 0.98 (d, C7 CH 1:7 Hz.).

Analysis.-Calcd for C I-1 C, 76.70; H, 9.36. Found: C, 76.44; H, 9.14.

Following this procedure but substituting the appropriate amounts of:

17;3-[ 1-methoxycyclohexl)oxy] -androsta-4,6-dien-3- one, 17 ;3-( l-cyclopenten-l-yloxy)-androsta-4,6-dien-3- one, and 17,B-[(tetrahydropyran-Z-yl)oxy]-androsta- 4,6-dien-3-one for androst-4,6-dien-3,17-dione cyclic 17-(ethylene acetal) resulted in the formation of:

175-[ l-methoxycyclohexyl) oxy] -7-methylandrost-5-en- 3-one, 17[3-( 1-cyclopenten-1-yloxy) -7methylandrost-5- en-3-one, and 7-methyl-17,B[ (tetrahydropyran-2-yl) oxy] -androst--en-3-one, respectively.

Example X 17B-hydroxy-6,7,8-dimethylandrost-5-en-3-one acetate A solution of 16.7 g. (0.0489 mole) of 17B-acetoxy-6- methyleneandrost 4 en-3-one and 8.2 g. sodium acetate in 330 ml. of absolute ethanol was stirred and refluxed overnight with 1.0 g. of palladium on charcoal. The mixture was filtered through diatomaceous earth, the filtrate concentrated, and diluted with water, and extracted with ether. The ether solution was dried over MgSO and removed under vacuum. Recrystallization of the residue from methanol gave 14.1 g. of 17,8 acetoxy 6 methylandrosta-4,6-dien-3-one: mp 171172.5 C.

A solution of lithium dimethylcopper was prepared under nitrogen by adding 55 ml. of 1.6 M (.088 mole) ethereal methyllithium solution to a slurry of 9.45 g. (.0495 mole) of cuprous iodide in 120 ml. of anhydrous ether at 0 C. The resulting solution was stirred at 0 C.

for an additional 20 minutes, followed by the addition of a solution of 5.0 g. (0.0146 mole) of 17fl-acetoxy-6-methylandrosta-4,6-dien-3-one in 65 ml. anhydrous tetrahydro furan. Stirring was continued for 70 minutes at 0 C. The reaction mixture was poured into a saturated aqueous ammonium chloride solution with vigorous stirring. Benzene was added and the mixture was filtered through diatomaceous earth. The organic layer was washed with a saturated aqueous ammonium chloride solution followed by a water wash, dried over MgSO treated with charcoal, filtered and concentrated to a pale yellow oil. The oil was dissolved in methylene chloride and chromatographed on 200 g. kieselguhr prepared in methylene chloride. One hundred ml. fractions of the eluate were col- 17fi-hydroxy-6,17u-dimethylandrosta-4,6-dien-3 -one,

17B-hydroxy-6,17a-dimethylandrosta-4,6-dien-3 -one,

acetate,

6-methylandrosta-4,6-dien-3,17-dione,

17fl-hydroxy-2a,6-dimethylandrosta-4,6-dien-3-one,

6-methyl-17a-[ (tetrahydtopyran-Z-yl oxy] -androsta-4,6-

dien-3-one,

1 8 17B-hydroxy-6-methyl-1711-( l-propynyl) androsta-4,6-

dien-3-one, and D-homo-17a/3-hydroxy-6,17au-dimethylandrosta-4,6-dien- 3-one.

The following 7-methylated steroids were obtained:

17,8-hydroxy-6,7, 17a-trimethy1androst-5-en-3-one,

17B-hydroxy-6,7,17u-trimethylandrost-5-en-3-one,

acetate,

6,7-dimethylandrost-5-ene-3,17-dione,

17 ,B-hydroxy-Za,6,7-trimethylandro st-5 -en-3 -one,

6,7-dimethyl-17B- (tetrahydropyran-Z-yl) oxy] -androst- 5-en-3-one,

17/3-hydroxy-6,7-dimethyl- 17 cc- 1-propynyl)androst-5- en-3-one, and

D-homo-17aB-hydroxy-6,7,17au-trimethyIandrOst-S-en- 3-one.

Example XI 17 fl-hydroxy-h-methylestr-5 -en3-one A solution of 25 g. (0.07 mole) of 3,17B-diacetoxy-3, S-estradiene in 25 ml. of pyridine and 250 ml. of acetic acid was cooled to 5 C. To this solution was added slowly with stirring 24 g. (0.075 mole) of pyridinium hydrobromide perbromide. When the color had disappeared the reaction mixture was poured onto a mixture of ice and Water and extracted with ether. The ether extract was quickly dried and was added under a steady stream of nitrogen to a refluxing mixture of 25 g. of lithium bromide and 25 g. of lithium carbonate contained in 400 ml. of dimethylformamide. Care was taken during the ether addition to maintain the temperature of the reaction mixture at C. After the ether had been completely removed the mixture was heated to reflux for one additional hour, poured onto a mixture of ice and water, and extracted with ethyl acetate. The organic extract was washed with water, dried over MgSO, and the solvent removed under vacuum. This crude oil was dissolved in 250 ml. of 10% methanolic potassium hydroxide and the solution refluxed for 45 minutes. The solution was concentrated, diluted with water, and extracted with ether. The resulting solid was recrystallized from an acetone-hexane solution to give 12 g. of 17,8-hydroxyestr-4,6-diene-3-one having a mp of 183-185 C.

A solution of lithium dimethylcopper was prepared under nitrogen by adding 158 ml. of 1.6 M (0.252 mole) ethereal methyllithium solution to a slurry of 26.7 g. (0.139 mole) of cuprous iodide in 500 ml. anhydrous ether at 0 C. The solution was stirred at 0 C. an additional 5 minutes and then a solution of 11.3 g. (0.042 mole) of 17,8 hydroxyestr 4,6-diene-3-one in 100 m1. anhydrous tetrahydrofuran was added over a 5 minute period. The reaction mixture was stirred an additional 5 minutes at 0 C. and poured into a saturated aqueous ammonium chloride solution. Benzene was added and the resulting mixture was rapidly filtered through diatomaceous earth. The organic layer was washed with a saturated aqueous ammonium chloride solution, with water, dried over MgSO and evaporated. The resulting oil was dissolved in methylene chloride and chromatographed rapidly on a silica gel column packed in methylene chloride. The desired material eluted with the methylene chloride solvent front and was twice recrystallized from an acetone-hexane solution to give the desired 17,8-hydroxy-7a-methylestr-5- ene-3-one: my 98101 C., UV max. (EtOH) none; IR (KBr) 1710 cm.- (C=O); NMR (CD01 65.51 (In, C6 H), 0.80 (d, C-7 CH J=7 Hz.).

{ Analysis.Calcd for C H O C, 79.12; H, 9.78. 'Found: C, 78.72, 78.57; H, 9.98, 9.92. f

Following the above procedure the appropriate equivalent amounts of the following compounds were substituted in lieu of the 17,8-hydroxy-estra-4,6-diene-3-one:

Estra-4,6-diene-3, l7-dione, 17w l-butynyl) -17,8-hydroxy-estra-4,6-diene-3 -one,

1 9 1 7,8-hydrxy-17a-( l-propynyl -estra-4,6-diene- 3-one, 17fl-hydroxyestra-4,6-diene-3-one, acetate, 17fi-[(tetrahydropyran-2-yl)oxy1-estra-4,6-diene-3-one, 17fi-hydroxy-17a-propylestra-4,6-diene-3-one, acetate, 17 a-butyl-l7fi-hydroxyestra-4,6-diene-3-one, 17oc-butyl-17/3-hydroxyestra-4,6-diene-3-one, acetate 17 a-butyl- 17fl-hydroxyestra-4,6-diene-3, 1 l-dione, acetate Estra-4,6-diene-3,l 1,17-trione, 6-methyl-l7fl-[ (tetrahydropyran-Z-yl) oxy] -estra-4,6-

diene-3-one and 13-ethyl-17fi-hydroxygona-4,6-diene-3-one, acetate.

13-ethyl-17fl-hydroxy-7-methylgon-5-ene-3-one, acetate.

EXAMPLE XII 17 fl-hydroxy-7fl-isopropylandrost-4-en-3-one A solution of lithium diisopropylcopper was prepared under nitrogen by adding 250 ml. of 2 M (0.5 mole) isopropyllithium in pentane to a slurry of 48.0 g. (0.25 mole) of cuprous iodide suspended in 250 ml. of anhydrous ether at 20 C. A solution of 30 g. (0.1 mole) 17fl-hyclroxyandrosta-4,6-diene-3-one in 500 ml. of anhydrous tetrahydrofuran was added dropwise. The reaction mixture was stirred for an additional 30 minutes at 20 C. an poured into 2 liters of 3 M HCl. Benzene was added and the mixture filtered through diatomaceous earth. The benzene layer was separated, washed with water, dried over magnesium sulfate and concentrated to dryness. The residue was dissolved in methylene chloride and chromatographed on a silica gel column packed in methylene chloride. The methylene chloride was concentrated to an oil which was crystallized three times from an acetonehexane mixture to give 17 8-hydroxy-7 8-isopropylandrost- 4-en-3-one: mp 153-156; UV max. (EtOH) 245 nm. (6 15,300); IR (KBr) 1670 cm:- (C=O); NMR (CDCI 8 5.75 (broad s, C-4 H).

Analysis.-Calcd for C H O C, 79.96; H, 10.37. Found: C, 79.86; H, 10.61.

EXAMPLE XIII 7u-methylandrost-5-ene-3,1 l, 17-trione 7fi-methylandrost-5-ene-3,1 l, l7-trione A solution of 30 g. (0.1 mole) androst-4-ene-3,l1,17-

itrione dissolved in 600 ml. of dioxane was saturated with gaseous HCl. To this solution was added a solution of 22.7 g. (0.1 mole) of 2,3-dichloro-5,6-dicyano-1,4-benzogmole) of ethereal methyllithium solution to a slurry of 38 g. (0.2 mole) cuprous iodide in 200 ml. of anhydrous ether at 0 C. The solution was stirred at 0 C. for an additional 10 minutes and a solution of 14.9 (0.05 mole) of androsta-4,6-diene-3,11,17-trione in 400 ml. of anhydrous tetrahydrofuran was added via dropwise addition. The reaction mixture was stirred for an additional 5 minutes at 0 C. and poured into 1 liter of a saturated aqueous ammonium chloride solution. Benzene was added and the mixture rapidly filtered through diatomaceous earth. The benzene layer was separated, washed with a saturated aqueous ammonium chloride solution, washed with Water, dried over magnesium sulfate and evaporated to dryness. The residue was layered with m1. acetone and the solid filtered. Two recrystallizations from acetone gave 70: methylandrost 5-ene-3,ll,17-trione; mp 198- 212 C. UVmax. (EtOH) 240 nm. (sh); IR (KBr) 1720, 1710-1680 cm.- (0:0); NMR (CDCl 6 5.42 (m, C-6 H), 0.98 (d, C-7 CH I'=12 Hz.).

Anaylsis.-Calcd for C H O- C, 76.40; H, 8.34. Found: C, 76.67; H, 8.55.

The first acetone mother liquor was evaporated and the residue chromatographed on a silica gel column packed in methylene chloride. The methylene chloride eluant was recrystallized from acetone-hexane to give 7ot-methylandrost-5-ene-3,l1,17-trione: mp 152-166"; UV max. (EtOH) 241 nm. (e 1270); IR (KBr) 1720, 1710-1680 cm.- (C=O); NMR (CDC13) 6 5.15 (broad t, C-6 H), 1.13 (d, C-7 CH J=l2 Hz.).

Analysis.-Calcd for C T-L 0 C, 76.40; H, 8.34. Found: C, 76.45; H, 8.48.

EXAMPLE XIV 7aunethyI-S- regnen-3,20-dione A solution of 31.4 g. (0.1 mole) of progesterone in 500 cc. of dioxane was saturated with gaseous HCl and added all at once to a solution of 22.7 g. (0.1 mole) of 2,3-

dichloro-5,6-dicyano-1,4-benzoquinone in 500 m1. dioxane saturated with gaseous HCl. The reaction mixture was stirred at room temperature for 15 minutes and filtered. Evaporation of the dioxane left a yellow oil which upon recrystallization from an acetone-hexane solution yielded 20 g. of pregna-4,6-diene-3,20-dione, having 2. mp of 132 C. A second recrystallization increased the mp to 128-130 C.

A solution of lithium dimethylcopper was prepared by the addition of 320 ml. of 1.6 M (0.512 mole) ethereal methyllithium under nitrogen at 0 C. to a slurry of 51 g. (0.268 mole) of cuprous iodide in 500 ml. of anhydrous ether. The solution was stirred at 0 C. for an additional 5 minutes and a solution of 20 g. (0.064 mole) of pregna- 4,6-diene-3,20dione in ml. anhydrous tetrahydrofuran was added over a period of 5 minutes. The mixture was stirred an additional 5 minutes and poured into 500 'ml. of a saturated aqueous ammonium chloride solution. Benzene was added and the mixture was rapidly filtered through diatomaceous earth. The organic layer was washed with a saturated aqueous ammonium chloride solution, washed with water, dried over MgSO and evaporated to dryness. The resulting solid was triturated with hexane and collected by filtration. Three recrystallizations from hexane gave the desired 7ot-methyl-5-pregnen-3,20- dione: mp 138-155 C. UV max. (EtOH) 238 nm. (sh); IR (KBr) 1685-1710 cm.- (0:0) NMR (CDC1 5 5.37 (m, C-6 H), 0.81 (d, C-7 CH 1:6.5 Hz).

Analysis.Calcd for C H 0 C, 80.44; H, 9.82. Found: C, 80.38; H, 9.73.

Following the above procedure an equivalent amount of the following compounds was substituted in lieu 'of the pregna-4,6-diene-3,20-dione: I

17a-hydroxypregna-4,6-diene-3,20-dione, 17a-methoxypregna-4,6'diene-3,20-dione, 1a,l6a-dimethylpregna-4,6-diene-3,20-dione, 17u-hydroxy-1a-methylpregna-4,6-diene-3,20-dione, 17a-hydroxy-l6a-methylpregna-4,6-diene-3,20-dione, 17a-hydroxy-6,1618-dimethylpregna-4,6-diene-35 1 1,20-trione, v Pregna-4,6-diene-3,11,20-trione, 1 1 17a-hydroxy-16-methylpregna-4,6-diene-3,11,20-trione,

17u-hydroxy-6-methylpregna-4,6-diene-3,11,20-trione,

20 8-hydroxypregna-4,6-diene-3-one,

l9-norpregna-4,6-diene-3 ,20-dione,

13-ethyl-17a-hydroxy-18,19-dinorpregna-4,6-diene-3,20-dione, acetate and 13 -ethyl- 17 a-hydroxy-6-methyl- 1 8-19-dinorpregna- 4,6-diene-3 ,20-dione,acetate.

The following compounds were respectively obtained:

17a-hydroxy-7-methylpregn-5-ene-3 ,20-dione, 17a-methoxy-7-methylpregn-5-ene-3 ,20-dione, 111,7,16ot-trimethylpregn-5-ene-3,20-dione, 17a-hydroxy-1a,7-dimethylpregn-5-ene-3,20-dione, 17u-hydroxy-7,16m-dimethylpregn-5-ene-3,20-dione, 17a-hydroxy-6,7,16,3-trimethylpregn-5-ene-3,1 1,20-trione, 7-methylpregn-5-ene-3 ,1 1-20-trione, 17a-hydroxy-7,16-dimethylpregn-5-ene-3 ,1 1,20-trione, 17a-hydroxy-6,7-dimethylpregn-5-ene-3 ,1 1,20-trione, 20/8-hydroxy-7-methylpregn-5-ene-3-one, 7-methyl-19-norpregn-5-ene-3,20-dione, 13-ethyl-17a-hydroxy-7-methyl-l8-19-dinorpregn- 5 -ene-3,20-dione, acetate and 13-ethyl-17u-hydroxy-6,7-dimethyl-18,19-dinorpregn- 5-ene-3,20-dione, acetate.

Example XV 17 a-acetoxy-6,7 a-dimethyl-5-pregn-3,20-dione A solution of lithium dimethylcoper was prepared by the addition of 260 ml. of 1.6 M (0.208 mole) ethereal methyllithium under nitrogen to a slurry of 41.6 g. (0.109 moles) of cuprous iodide suspended in 600 ml. of anhydrous ether at C. The mixture was stirred at 0 C. for 10 minutes after which a solution of 20.0 g. (0.026 mole) of 17a acetoxy 6 methyl pregna 4,6 diene 3,20 dione in 100 cc. anhydrous tetrahydrofuran was added over a -minute period. After stirring at 0 C. for an additional 5 minutes, the reaction mixture was poured into a saturated aqueous ammonium chloride solution. Benzene was added and the mixture rapidly filtered through diatomaceous earth. The organic layer was washed with a staturated aqueous ammonium chloride solution, washed with water, dried over MgSO and concentrated under vacuum. The residual oil was dissolved in methylene chloride and rapidly filtered through a silica gel column packed in methylene chloride. The first eluant was recrystallized from an acetone-hexane mixture to give 17a-acetoxy-6,7-ot-dimethyl-5-pregnene 3,20 dione; mp 140-160 C.; UV max. (EtOH) 235 nm. (e 2020); IR (KBr) 1700 (C=O) 1720 (0:0) 1725 cm.- (ester C=O); NMR (CD01 6 1.65 (s, C-6 CH 0.91 (d. C-7 CH J-=6.5 Hz.).

Analysis.-Calcd for C H O C, 74.96; H, 9.06. Found: C, 74.17, 74.24; H, 9.05, 9.04.

In accordance with the foregoing procedure an equivalent amount of the following compounds was substituted in lieu of the 17a-acetoxy-6-methyl-pregna-4,6-diene-3,20 dione:

6-methylpregna-4,6-diene-3 ,20-dione,

17a-hydroxy-6-methylpregna-4,6-diene-3,20-dione, 6,17a-dimethylpregna-4,6-diene-3,20-dione, 16a,17a-dihydroxypregna-4,6-diene-3,20-dione cyclic acetal with acetone, 16oz,17a-dihydroxy-6-methylpregna-4,6-diene3,20-

dione cyclic acetal with acetone, 17a-methoxy-16-methyllenepregna-4,6-diene-3 ,20-dione, 17a methoxy 6 methyl 16 methylenepregna 4,6

diene-3,20-dione, 17a-hydroxy-16-methylenepregna-4,6-diene-3,20-dione, 16u-methylpregna-4,6-diene-3,20-dione, 6,l6a-dimethylpregna-4,6-diene-3,20-dione, and 6,16u-dimethylpregna-4,6-diene-3,1 1,20-trione.

The following compounds were respectively obtained:

4 6,7-dimethylpregn-5-ene-3,20-dione,

17a-hydroxy-6,7-dimethylpregn-5-ene-3,20-dione,

22 6,7, l7a-trimethylpregn-5-ene-3,20-dione, 16a-17ot-dihydroxy-7-methylpregn-5-ene-3,20-

dione cyclic acetal with acetone, 16a,l7a-dihydroxy-6,7-dimethylpregn-5-ene-3,20-

dione cyclic acetal with acetone, 17a-methoxy-7-methyl-1 6-methylenepregn-5-ene- 3,20-dione, 17u-methoxy-6,7-dimethyl-16-methy1enepregn-5- ene-3,20-dione, 17a-methoxy-7-methyl-16-methylenepregn-5-ene- 3,20-dione, 7,16a-dimethylpregn-5-ene-3,20-dione, 6,7,16u-trimethylpregn-5-ene-3,20-dione, and 6,7 1 6 u-trirnethylpregn- 5-ene-3, 1 1,20-trione.

EXAMPLE XVI 7a-methyl-9,8,10ot-pregn-5-ene-3,20-dione A solution of lithium dimethylcopper was prepared under nitrogen by adding 76.5 ml. of 1.6 M (0.122 mole) ethereal methyllithium to a slurry of 12.15 g. (0.064 mole) of cuprous iodide suspended in ml. of anhydrous ether at 0 C. This solution was stirred at 0 C. for 5 minutes to which a solution of 4.5 g. (0.0153 mole) of 9B,10a-pregna-4,6-diene-3,20-dione in 100 ml. of anhydrous tetrahydrofuran was added dropwise over a period of two minutes. The mixture was stirred for an additional 8 minutes and poured into 250 ml. of a saturated aqueous ammonium chloride solution. Benzene was added and the mixture rapidly filtered through diatomaceous earth. The benzene layer was washed with a saturated aqueous ammonium chloride solution, washed with Water, and dried over MgSO Removal of the solvent under vacuum gave an oil which was dissolved in methylene chloride and rapidly chromatographed through a silica gel column packed in methylene chloride. The material which eluted with the solvent front was layered with hexane and filtered. Upon recrystallization from hexane the desired 7a-methyl-9fi,10ot-pregn-5-ene-3,20 dione was obtained. mp 112116 0; UV max. (EtOH) 287 nm. (e 5.2); IR (KBr) 1710-1685 cm.'" (C=O); NMR (CD01 6 5.36 (m, C-6 H), 0.96 (d, C-7 CH 1:7 Hz.).

Analysis.Calcd for C H O C, 80.43; H, 9.82. Found: C, 80.21, 80.35; H, 9.80, 9.57.

Following this procedure an equivalent amount of the following compounds was substituted in lieu of 9 3,10u pregna-4,6-diene-3,20-dione:

20B-hydroxy-9fi,10a-pregn-4,6-diene-3-one,

6-methyl-9B,10u-pregna-4,6-diene-3,20-dione,

17a-hydroxy-9B,10a-pregna-4,6-diene-3,20-dione, and

16oz,17a-dihydroxy-918,10ot-pregna-4,6-diene-3,20-dione cyclic acetal with acetone.

The following compounds were correspondingly obtained:

20fi-hydroxy-7-methyl-9fl,10a-pregn-5-ene-3-one,

6,7-dimethyl-95,10a-pregn-5-ene-3,20-dione,

17ot-hydroxy-7-methyl-9 8,10tat-pregn-5-ene-3,20-dione,

and

16.x,17tx-dihydroxy-7-methyl-9p,10u-pregn-S-ene-3,20-

dione cyclic acetal with acetone.

The same procedure was followed but in lieu of 9fi,10a- 4,6-diene-3,20-dione the following 9,8,10wpregna-androsta-4,6-diene-3-ones were employed:

17B-hydroxy-4-methyl-9,10u-androsta-4,6-diene-3-one,

17,8-hydroxy-4,17a-dimethyl-9fi,10a-androsta-4,6-diene- 3-one,

- 17fl-hydroxy-6-methyl-9/3,10a-androsta-4,6-diene-3-one,

17 B-hydroxy-9 8, la-androsta-4, 6 -diene -3-orie,

propionate,

17fi-hydroxy-9p,10rx-androsta-4,6-diene-3-one, hydro cinnamate, and

l75-hydroxy-9fl,10a-androsta-4,6-diene-3-one, hydrosuecinate.

The following compounds were correspondingly obtained:

17,8-hydroXy-4,7-dirnethyl-9,8,10oc-androst--ene-3-one,

17 B-hydroxy-4,7, 17 u-trimethyl-9 5, a-androst-5-ene-3 one,

17 8-hydroxy-6,7-dimethyl-9fi,10u-androst-5-ene-3-one,

7-rnethyl-9B,10a-androst-5-ene-3,17-dione,

17 ,S-hydroxy-7-methyl-17 a- (Z-methylallyl) -913,1Uocandrost-5-ene-3-one,

17fi-hydroxy-7-methyl-9 3,lOa-androst-S-ene-3-one,

1 7B-hydroxy-7-methyl-9p, l0aandrost-5 -ene-3 -one,

acetate,

17p-hydroxy-7-methyl-9B, 10a-androst-5-ene-3-one,

propionate,

17fl-hydroxy-7-methyl-9B,10u-andr0st-5-ene-3-one,

hydrocinnamate, and

17/3-hydr0xy-7-methyl-9B,10m-androst-5-ene-3-one,

hydrosuccinate.

EXAMPLE XVII An illustrative preparation of 10,000 tablets, each containing 10 milligrams of 1ffi-hydroxy-h-methylandrost- 5-ene-3-one is prepared as follows:

Gm. 1'lfl-hydroxy-7amethylandrost-5-ene-3-one 100 Lactose 1000 Starch paste (10% w./v. starch in water) 100 Starch 32.5 Calcium Stearate 6.5

EXAMPLE XVIII An illustrative composition for the preparation of 1,000 two-piece hard gelatin capsules, each capsules containing 1.0 milligrams of l7fi-hydroxy-7a,17rx-dimethylandrost-5- ene-3-one is prepared as follows:

Gm. 17B-hydroxy-7u,17a-dimethylandrost-5-ene-3-one 1.00 Corn starch 150 Magnesium stearate 25 Hard gelatin capsules 1000 The finely powdered ingredients are mixed until uniformly dispersed and filled into hard shell gelatin capsules of the appropriate size.

Similarly soft gelatin capsules may be prepared in which the above composition can be granulated, slugged or compressed directly into the rotary die or plate mold in which the soft gelatin capsule is formed.

EXAMPLE XIX 1000 grams of an ointment for topical application containing 0.1% of 7a-methyl-S-pregnen-3,20 dione can be prepared from the following ingredients:

7a-methyl-5-pregnen-3,20-dione 1 Light liquid petrolatum 250 Wool fat 200 White petrolatum q.s. ad 1000 The wool fat, white petrolatum and 200 gms. of the light liquid petrolatum are liquified and held at 110 F.

L R5 17 R1 1 g (CHI) 11 OQJM R;

wherein R is selected from the group consisting of hydrogen and (at or [3) -methyl with the proviso that when R is a-methyl and the 9-hydrogen is in the p-position, and when R is fi-methyl the 9-hydr0gen is in the a-position;

R is individually selected from the group consisting of hydrogen and (a or id-methyl;

R is hydrogen or methyl;

R is an (a or m-loweralkyl group having from 1 to 3 carbon atoms inclusiyely;

R is hydrogen or oxo;

R is selected from the group consisting of hydrogen,

methyl and ethyl;

R is selected from the group consisting of hydrogen, loweralkyl, alkenyl, alkynyl, alkadienyl, alkenylnyl and alkadiynyl, each having from 1 to 6 carbon atoms inclusively;

R is selected from the group consisting of hydrogen l-cyclopenten-l-yloxy, l-methoxycyclohexyloxy, 2- tetrahydropyranyloxy, and the group -OR wherein R represents hydrogen or an acyl radical having from 1 to 12 carbon atoms inclusively with the proviso that R-; and R cannot both be hydrogen, that when R; is unsaturated R cannot be the -OAcyl group, and with the further proviso that R, and R when taken together are 0x0 or a cyclic ethylene acetal; and

n is the integer 1.

2. 17,8-hydroxy-7a-methylandrost-5-en-3-one.

3. 6,70: dimethyl 17,6 hydroxy-17a-(1-propynyl) androst-S-en-B-one.

4. A process of preparing 3-keto-7(a,fl)-loweralkyl-A androstanes, wherein the loweralkyl group contains from 1 to 3 carbon atoms inclusively, which comprises dissolving an organocopper reagent selected from the group consisting of diloweralkyllithium cuprate, a complex of loweralkylcopper with trialkylphosphite and a complex of loweralkylcopper with trialkylphosphine, wherein each of said alkyl and loweralkyl groups contains from 1 to 3 carbon atoms inclusively, in an inert anhydrous organic solvent, reacting said organocopper reagent with an appropriate 3-keto-4,6-androstadiene at a temperature of from about 10 to about -78 C. until the reaction is complete, and isolating the 3-keto-7(er,p)-lowerall :yl-A- androstane so obtained. 0

wherein 5. A process of preparing 3-keto-7( a,B)-loweralky1-A androsta'nes according to claim 4'wherein the 3-keto-4,6- androstadienes have the general formula R is selected front the group consisting of hydrogen and (a, or }8)-methyl with the proviso that when R is e-methyl the 9-hydrogen is in the it-position, and when R is fi-methyl the 9-hydrogen is in the a-position;

R is individually selected from the group consisting of hydrogen and (a or fi)-methyl;

R is hydrogen or methyl;

R is hydrogen or 0x0;

R is selected from the group consisting of hydrogen,

methyl and ethyl;

R is selected from the group consisting of hydrogen, loweralkyl, alkenyl, alkynyl, alkadienyl, alkenylnyl and alkadiynyl, each having from 1 to 6 carbon atoms inclusively;

R is selected from the group consisting of hydrogen l-cyclopenten l yloxy, 1-methoxycyclohexyloxy, Z-tetrahydropyranyloxy, and the group -OR wherein R represents hydrogen or an acyl radical having from 1 to 12 carbon atoms inclusively with the proviso that R, and R cannot both be hydrogen, that when R, is unsaturated R cannot be the -OAcyl group, and with the further proviso that R; and R when taken together are 0x0 or a cyclic ethylene acetal; and

n is the integer 1.

6. A 3-keto-7(c p)-loweralkyl-A -steroid having the general formula H3 Risa wherein R is selected from the group consisting of hydrogen and (a or [SO-methyl with the proviso that when R is ot-methyl the 9-hydrogen is in the fl-position, and when R is p-methyl the 9-hydrogen is in the zx-POSition;

R is individually selected from the group consisting of hydrogen and (a or fad-methyl;

R is hydrogen or methyl;

R, is (a or SD-loweralkyl group having 1 to 3 carbon atoms inclusively;

R is hydrogen or 0x0;

R is selected from the group consisting of hydrogen,

methyl and ethyl;

R is selected from the group consisting of hydrogen,

methyl and methylene;

R is selected from the group consisting of hydrogen,

methyl, ethyl, Z-tetrahydropyranyloxy and the group OR,,, wherein R represents hydrogen, a loweralkyl group having from 1 to 3 carbon atoms inclusively, and an acyl radical having from 1 to 12 carbon atoms inclusively, with the proviso that when R is methylene, R cannot be the --O-acyl group, and with the further proviso that R and R when taken together represent the l6a,l7a-alkylidenedioxy group wherein A and B are each loweralkyl having from 1 to 4 carbon atoms inclusively;

R is selected from the group consisting of hydrogen, l-cyclopenten 1 yloxy, l-methoxycyclohexyloxy, Z-tetrahydropyranyloxy and the group --OR wherein R represents hydrogen and an acyl radical having from 2 to 12 carbon atoms inclusively, and which when taken together with R is 0x0;

R is hydrogen with the proviso that R and R cannot both be hydrogen, and which when taken together with R is 0X0; and

n is the integer 1.

7. l7e-hydroxy-7a-methylpregn-5-ene-3,20-dione acetate.

8. 17a hydroxy-6,7a-dimethylpregn-5-ene-3,20 dione acetate.

9. A process of preparing 3-keto-7(a,/8)-loweralkyl-A pregnanes, wherein the loweralkyl group contains from 1 to 3 carbon atoms inclusively, which comprises dissolving an organocopper reagent selected from the group consisting of diloweralkyllithium cuprate, a complex of loweralkylcopper with trialkylphosphite and a complex of loweralkylcopper with trialkylphosphine, wherein each of said alkyl and loweralkyl groups contains from 1 to 3 carbon atoms inclusively in an inert anhydrous organic solvent, reacting said organocopper reagent with an appropriate 3-keto4,6-pregnadiene at a temperature of from about 10 to about 78 C. until the reaction is complete, and isolating the 3-keto-7(a,;3)-loweralkyl-A pregnane so obtained.

10. A process of preparing 3-keto-7(a,fi)-loweralkyl- A -pregnanes according to claim 11 wherein the 3-keto- 4,6-pregnadienes have the general formula wherein R is selected from the group consisting of hydrogen and (a or m-methyl with the proviso that when R is a-methyl the 9-hydrogen is in the [3-position, and when R is (it-methyl the 9-hydrogen is in the e-position;

R is individually selected from the group consisting of hydrogen and (a or ,B)-methyl;

R is hydrogen or methyl;

R is (a or fi)-loweralkyl group having 1 to 3 carbon atoms inclusively;

R is hydrogen or 0x0;

R is selected from the group consisting of hydrogen,

methyl and ethyl;

R is selected from the group consisting of hydrogen,

methyl and methylene;

. 23 R is selected from the group consisting of hydrogen, n is the integer 1; i v r. methyl, ethyl, Z-tetrahydropyranyloxy and the group 11. 17fl-hydroxy-7-rnethylester-5-ene=3 one, acetate;

--OR WhereinR represents hydrogen, aloweralkyl ,1 a .4 A group having from 1 to 3 carbon atoms inclusively, References Cited ifmi in f 133 ii -ti 135322???) tiaiwiin 5 UNITED STATES PATENTS a C llSlV 1 10 I a methylene, R cannot be the --acyl group, and et a1 with the further proviso that R and R when taken 3498975 3/1970 r I 3 5 together represent the 16u,17a-a1ky1idenedioxy group 3711522 1/1973 g i 6: '7 4 3,262,949 7/1966 Ringold 'et' al; 260397:3 /c\ 3,346,570 10/ 1967 Anner eflal. 260-239.55 A OTHER REFERENCES wherein A and B are each loweralkyl having from Fieser et 1 Steroids, 5 1 to 4 carbon atoms rnelusively;

R is selected from the group consisting of hydrogen, HEN FRENCH, primaryiExaminer W l-cyciopenten 1 yloxy, l-methoxycyclohexyloxy, V Z-tetrahydropyranyloxy and the group OR where- VU.S. 1C1; X.'R. if ,l V p in R represents hydrogen and an acyl radical havf i ing from 1 to 12 carbon atoms inclusively, and which 29 ggg 239'55 3 when taken together with R is 0x0;

R is hydrogen with the proviso that R and R cannot both be hydrogen, and which when taken together with R is 0x0; and

UNITED STATES PATENT OFFICE CERTIFICATE 'OF CORRECTION PATEN? NO. 3,833,621

DATED September 3, 197% INVENIORt'St Joyce F Grunwel l, Harvey D Benson and 9 Vladimir Petrow It IS certlfled that error appears In the above-ldentlfled patent and that sald Letters Patent are hereby corrected as shown below:

Column 2, l ine 1, "androstant, 19-nor-androstan" should read --androstane, l9-nor-androstane--.

Column 5, l ine 39, "compound" should read "compounds" Column 3, line 65, "dimethyltestosteroneterone" should read --dimethyltestosterone--=.

Column 6, line 29, "dienese" should read --dienes-.

Column 6, line 40, "diloweralkyllthium" should read -=-diloweralkyll ithium".

Column 7, line 58, "100 C," should read --10 C Column 9, l ine 10, the portion of structure IX H CH3 1! (3H8 13 13 0 should read c \RIO I 12 Column 9, line 35, "abient" should read --ambient--.

Column 10, line 9, where where should read --where--.

Column 10, line 16, "mole" should read --male--.

Column 11, l ines 24 and 25 should read =-Parenteral suspensions are prepared in a similar manner except that the steroid is suspended in the vehicle and UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,853,621 Page 2 DATED 3 September 5, 1974 INVENTOR(S) Joyce F. Grunwell, Harvey D. Benson and It is certlfledYhflrhWa'pEeaFfiFtlhQ'bove-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 12, l ine 70, "1,4" should read --1, l--.

Column 12, l ine 75 "eluated" should read --eluted--.

Column 15, l lne 5, "10 ml should read --1OO ml Column 13, l ine 24, EtOH) nm. should read EtOH) 240 nm.--.

Column 17, l lne 25, "6,73 should read --6,7q--

Column 18, line 65, "my" should read --mp--.

Column 18, line 67, "CH should read --CH Column 21, l ine 28, "dimethylcoper' should read --dimethylc opper--.

Column 21, l ine 41, staturated" should read --saturated--.

Column 21, line 65, "methyllenepregna" should read =--methylenepregna-.

Column 22, l ine 10, "17d-methoxy" should read --17 -hydroxy--.

Column 22, l ine 61, "9B, 10 should read --9B,10g,- pregna- Column 22, l ines 62 and 65, 9Q,lO -pregna-androsta" should read --9 ,10 ,-androsta- UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATEN'l' NO. 3,833,621 r Page 1 3 DATED 1 September 3, 1974 j v 5 Joyce F Grunwel l, Harvey D Benson and Vladimir Petrow it is certrfied that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 21 (Claim 1), l ine 31, "and the 9-hydrogen should read --the 9hydrogen--.

Column 26 (body of Claim 10), line l l, "claim 11" should be renumbered --claim 9-. (Claim 10 was originally submitted as claim 12) Signed and sealed this 17th day of June 1975.

SEAL) Att st:

e C. MARSHALL DANN Commissioner of Patents RU H C. WAON T a and Trademarks Attesting Officer 

